Background: In response to evidence of serious harms and modest benefits associated with long-term opioid therapy (LTOT), 2016 guidelines from the Centers for Disease Control and Prevention (CDC) and 2017 guidelines from the Department of Veterans Affairs (VA) and Department of Defense (DoD) recommend limiting the frequency, intensity, and duration of opioid prescribing. For patients on LTOT, these guidelines recommend tapering to reduced doses or discontinuation if benefits do not clearly outweigh harms. VA initiatives to implement guideline recommendations have increased opioid reduction in practice and decreased prevalence of LTOT, but effects on patients are unclear. Research is needed to understand long-term effects of LTOT reduction or discontinuation on patients and how different treatment approaches may affect results. Significance/Impact: Intended benefits of opioid reduction include improved function and quality of life and decreased risk of overdose and death. Unintended negative consequences?such as worsened function and increased risk of suicide?have been identified as potential harms, especially for high-risk patients or when opioids are reduced in an abrupt or unsupported manner. Research is needed to better understand effects over time of opioid prescribing and pain care practice changes on patient-centered outcomes, including pain- related function, quality of life, and mortality. Innovation: The Effects of Prescription Opioid Changes for Veterans (EPOCH) study is a prospective longitudinal cohort study of VA patients treated with LTOT and a unique resource for understanding patient outcomes of pain care practice changes. VA HSR&D funding supported establishment of a nationwide population cohort of 271,892 VA patients treated with LTOT for at least 6 months before a 2016 index date. A two-stage stratified sampling design was used to identify a representative sample of patients who were invited to participate in a mixed-mode (mail and phone) survey. Of 14,160 patients invited, 9253 (65.3%) enrolled in the survey panel. This project will expand analyses and extend long-term follow-up to a total of five years. Specific Aims: The main objective of this study is to understand dynamic effects of changes in opioid prescribing on patient-reported outcomes and mortality over time. Specific aims are to: 1) examine associations over five years of time-varying opioid dose with pain-related function (primary outcome) and quality of life; 2) examine different approaches to opioid dose reduction by a) characterizing patient subgroups with distinct trajectories of opioid treatment over time and then b) evaluating associations of opioid treatment trajectories with pain-related function (primary outcome) and quality of life; and 3) examine associations of time-varying opioid dose with all-cause mortality and survival. Methodology: This study will continue annual survey waves with patients in the existing survey panel at 48 and 60 months after baseline, using a multiple-contact approach that has proven effective so far. Follow-up questionnaires will include repeated measures of pain-related function and health-related quality of life as the primary patient-reported outcomes. Health services, covariates, and outcome data from VA administrative databases will be merged with patient-reported data from questionnaires. Analyses will use data for two panels of VA patients treated with LTOT? the survey sample of 9253 patients (aim 1 and aim 2b) and the full population cohort of 271,892 patients (aim 2a and aim 3). Implementation/Next Steps: Next steps depend on the actual results, but we expect findings to be important to VA leaders, prescribing clinicians, and patients with chronic pain. We will maintain communication throughout the project with VA program partners to share findings in a timely manner. We will collaborate with a Veteran Engagement Panel on development of patient-centered dissemination approaches. If results demonstrate clear best practices, we will develop and test interventions to implement them in clinical practice.